Dr Allister Grant MRCP, PhDConsultant HepatologistLeicester Royal Infirmary

Anything New in PSC?

Primary Sclerosing Cholangitis

• Chronic progressive cholestatic liver disease

• Median survival between 12 and 18yrs• Biliary Stricturing• Cholangitis• Cholangiocarcinoma prevalence 6-20%

incidence 1-5% / year

Martin et al Ann Surg 1990, Ponsioen et al Gut 2002, Boberg et al Scand J Gastro 2002

PSC Cirrhosis

Expanded Portal Tracts(Blue)

2-10% of IBD patients will develop PSC

~ 70% of PSC patients have evidence of IBD

IBD and PSC

Pathogenesis of PSC

• Multifactorial/ Complex

• Cellular immunity

• Autoimmunity?

• Bacterial Antigens

• Aberrant Lymphocyte Homing

• Cytokines

AETIOLOGY OF PSC?

HLA polymorphisms

PSC A1, B8, DR3, DQ2

HLA haplotypes and primary sclerosing cholangitis

HLA haplotypes

negatively associated

with PSC

HLA haplotypesassociated with PSC

HLA haplotypes with strong associationwith PSC

DRB1*04-DQA1*03-DQB1*0302 DRB1*03-DQA1*0501-DQB1*02DRB1*13-DQA1*0103- DQB1*0603DRB1*15-DQA1*0102-DQB1*0602Cw*0701-B8-DRB1*0301B8-MICA5.1-MICB24-DR3

DRB1*03-DQA1*0501-DQB1*02

Other gene polymorphism• CTLA-4• CCR5• IL-1• IL10• MMP-3

AETIOLOGY OF PSC?

DR2 associated with younger onset

DR4 associated with rapid disease progression

Donaldson Hepatol 1991, Mehal Gastro 1994

Autoimmunity

• 2:1 M:F ratio and poor response to immunosupression imply PSC is not a classical autoimmune disease

• PSC is associated with the “autoimmune” haplotype

• 25% of PSC patients have 1 autoimmune diseasec.f. 4% of IBD Saarinen Am J Gastro 2000

AETIOLOGY OF PSC?

Autoantibodies

AETIOLOGY OF PSC?

Anti-nuclear antibody (ANA) 7–77% Anti-smooth muscle antibody (ASMA) 13–20% Anti-endothelial cell antibody (AECA) 35% Anti-cardiolipin antibody 4–66% Thyroperoxidase 7–16%Thyroglobulin 4%Rheumatoid factor 15%

NB: note antimitochondrial antibody is only rarely detected in PSC (-10%). This is useful in differentiating PSC from PBC

Antibody Prevalence

• To date there is no convincing model of the pathogenesis of PSC that implicates Anti-Neutrophil Ab’s

Atypical p-ANCA (p-ANNA)

• Monoclonal Ab to colonic epithelial protein in UC can cross react with biliary epithelial cells in patients with PSC and UC- ? Common antigen Mandal et al Gastro 1994

AETIOLOGY OF PSC?

Bacterial Antigens

AETIOLOGY OF PSC?

Investigation confounded by contamination of bile duct at ERCP

Rats develop hepatic injury similar to PSC after artificially induced SBBO

Lichtman et al Gasto 1990

Bacterial peptides instilled rectally in rats with a chemical colitis appear quickly in bile and Initiate small duct cholangitis

Yamada et al J Gastro 1994

Aberrant Lymphocyte Homing

AETIOLOGY OF PSC?

Transmigration Tethering Rolling Arrest & Activation

Endothelium

Blood Flow

Lymphocyte

Selectins Integrins Integrins & Chemokine receptors Chemokine receptors

ChemokinesAddressins & ChemokinesCarbohydrate ligands Addressins

Adhesion cascade

BLOOD TISSUE Lymph Node BLOOD

Naïve T cell

Memory T cell

Memory T cell

Skin

Gut

I Weissman, E Butcher, C Mackay, S Shaw and S Jalkanen

TISSUE SPECIFIC HOMING OF MEMORY EFFECTOR

T LYMPHOCYTES

Gut Endothelium

MAdCAM-1 VCAM-1

Flow

CD3+

CD3+CD4/8+

Tissue specific T cell recruitmentGrant AJ Lancet 2002

CXCR3 + VAP-1r

VAP-1

IP-10

MAdCAM-1

CCL25(TECK)

NORMAL LIVER GUT

CCR9 + 47

VAP-1 MAdCAM-1

IP-10

INFLAMED PSC LIVER

?

Tissue specific T cell recruitmentGrant AJ Lancet 2002, Eksteen B, Grant AJ et al JEM 2004,

Eksteen B, Adams DH Nat Rev Immunol 2006

CXCR3 + VAP-1r

VAP-1

IP-10

MAdCAM-1

CCL25(TECK)

NORMAL LIVER GUT

CCR9 + 47

VAP-1 MAdCAM-1

IP-10

INFLAMED PSC LIVER

TECK

Diagnosis of PSC

• Most diagnoses are made after the discovery of abnormal LFT’s at IBD FU

• Cholestatic LFT’s (normal or fluctuating)

• Atypical p-ANCA -in 33-88%

• Abnormal MRCP or ERCP

• Liver Biopsy

Small Duct PSC

• Subgroup of PSC

• Normal ERCP/MRCP

• Typical histological changes

• Benign course- only 12 % progress to classical PSC

• No reports of CholangioCa

• Similar rates of IBD (? CD>UC)

UDCA in PSC

• Widely used in cholestatic liver disease• Hydophilic• Mechanisms of action unclear

• Hydrophobic bile acids are toxic• Probably not a detergent effect• May cause damage by Fas-mediated apoptosis

NTCP

OATP

UDCA – Mechanism’s of Action

• Displaces hydrophobic bile acids• Choleretic effect• Small amounts normally present• 80% absorbed through small bowel• Reduced bioavailability in cholestasis

UDCAUDCAGLY

TAUBSEP

Portal BloodHepatocyte

Canniliculus

UDCA – Mechanism’s of Action

Trials of UDCA in PSC

• Limited good quality trials

• Small numbers

• Short follow up

Summary of trials of UDCA in PSC

Cullen S APT 2005

Immunosupression in PSC

• SteroidsNo significant effect

• Methotrexate3 small trials- no added effect over UDCA

• AzathioprineNo published Trials

• CiclosporinOne RCT 2yrs 34pts- prevented histological progression but no improvement in LFT’s

Immunosupression in PSC

• TacrolimusOne study of 10 pts, improved LFT’s but progression not assessed

• Mycophenolate MofetilOne small trial –Mayo 30 pts 1 yr- no significant effect

• Metronidazole 6-800mg + UDCA 15mg/kg80 pts- MTZ sig improved ALP but no significant effect on progression

• Colchicine, Penicillamine, Etanercept, Nicotine No significant effects

Immunosupression in PSC

• Combination Rx

• UDCA 500-750/d +• Prednisolone 1mg/kg/d +• Azathioprine 1-1.5 mg/kg/d

• Median 41 mo• All had biochemical improvement• 6/10 had histological improvement• Only 1/10 had radiological deterioration

Schramm et al Ann Int Med 1999

Biliary Strictures and Cholangiocarcinoma

Dominant Strictures

– Extrahepatic ducts

– Prevalence 35-45%

– Stenting or dilatation? Increasing evidence that

dilatation>stenting Peterson Am J Gast 2001,Stiehl J Hepatol

2002

– Antibiotic prophylaxis

Dominant StricturesStiehl et al Eur J Gastro Hepatol 2006

• 50 patients (103 ERCP’s)

• At ERCP 37 had a dominant stricture

• Culture of bile revealed 15/37 (40%) of those with DS were infected with enteric bacteria

• The 13 controls without a DS had sterile culture

• Positive cultures were associated with a significant deterioration in bilirubin over the following 7mo (median)

Dominant StricturesBjornsson et al Am J Gast 2004

• Natural Hx study

• ERCP’s form 125 pts with PSC

• 56 (45%) dominant strictures

• No significant difference in ALP between those with and without a DS

• The change in ALP/Bili when comparing pre ERCP values to 2-12 mo post ERCP was not significantly different in those with and without a DS

Cholangiocarcinoma

• Prevalence 6-20%

• Incidence 1-5% / year

• Prediction is extremely difficult

• Independent risk factors– Clincal suspicion……..Cullen APT 2005– Recent diagnosis– No previous UDCA– Previous Colon Ca– Variceal bleeding…….Burak et al Am J Gast 2004– Proctocolectomy– Lack of symptoms

Investigation

• Dilated intrahepatic ducts on USS/ tumour compression or thrombosis of PV

• Mass on X-sectional imaging• ERCP• Brush Cytology• Needle Biopsy• ?EUS and Intraductal ultrasonography• ?PET• Ca19.9

• Level >100 U/ml…. Sensitivity 75%, specificity 80%

Cholangiocarcinoma

Cytology

• High specificity and PPV (92-100%)• Low sensitivity (50%) and NPV

• May be improve in future by molecular methods

• Inactivated tumour supressor genes• Dysregulation of apoptosis

Cholangiocarcinoma

“ This is not the end. This is not even the beginning of the end. But it is, perhaps, the end of the beginning”

Winston Churchill(1942)